Hypoxia-induced deacetylation is required for tetraploid differentiation in response to testicular ischemia-reperfusion (IR) injury.

Accumulated understanding of epigenetic modifications during ischemia-reperfusion (IR) injury suggests that additional targeted approaches and novel mechanisms that have not been explored in the reproductive system underlie the pathogenesis. Here we show, with a standard murine model of testicular IR, ischemia-induced histone deacetylase (HDAC) activity in the testis with concomitant reduction in histone acetyl transferase activity in vivo. Pretreatment with chemical HDAC inhibitors significantly induced apoptosis in tetraploid pachytene spermatocytes during ischemic insult and thereafter resulted in attenuated meiotic differentiation. We also identified the distinct HDACs involved in primary spermatocytes upon hypoxic stress. In vitro, elevated expression of HDAC2 was physiologically associated with p53, a master regulator believed to be a guardian of genome integrity during spermatogenesis. p53-mediated apoptosis was inhibited by deacetylation of p53 in differentiating pachytene spermatocytes in response to ischemic stress. Overall, the current data suggest that hypoxia-induced deacetylation may operate as an indispensible defensive mechanism for meiotic differentiation during the ischemic period of IR testis, thus pointing to a novel therapeutic target for future medical intervention.